1. Field of the Invention
The invention relates to novel 4-cyclohexyl substituted 1,3,2-oxazaborolidine chiral accessories of (R) and (S) configurations and processes for producing and using them. More particularly, the present invention relates to a process for an enantioselective reduction of prochiral ketones to chiral secondary alcohols using the novel chiral accesories.
2. Description of Related Art
Chiral accessories of formula A, which are useful for catalyzing an enantioselective reduction of ketones by borane, are well known in the art. See e.g., Tetrahedron: Asymmetry, Vol. 5, No. 2, pp. 165-168 (1994); Tetrahedron: Asymmetry, Vol. 5, No. 3, pp. 465-472 (1994); Tetrahedron: Asymmetry, Vol. 9, No. 7, pp. 1091-1095 (1998); Tetrahedron: Asymmetry Report Number 13, Vol 3, No. 12, pp. 1475-1504 (1992); Tetrahedron: Asymmetry, Vol. 7, No. 11, pp. 3147-3152 (1996); and SynLett, pp. 273-274 (March, 1997). 
where,
R1 is an alkyl or aryl group,
R2 is an alkyl or aryl group,
R3 is a hydrogen atom or an alkyl, aryl, aralkyl or alkoxy group.
These chiral accessories are generally prepared from enantiomerically pure amino acids. Consequently, only compounds having absolute (S) configurations can generally be prepared inexpensively, since only (S)-amino acids are typically found in nature. In contrast, (R)-amino acids are usually relatively expensive, because they are generally not found in nature and must be prepared either de novo, which entails separation from racemic mixtures, or by expensive enantioselective routes.
Many useful pharmaceutical agents require for their manufacture, chiral secondary alcohol intermediates having an absolute configuration which is introduced by means of the chiral accessories of type A having the (R) absolute configuration. It is obviously a disadvantage that expensive (R)-amino acids are required for the manufacture of many useful pharmaceutical agents. One of the few inexpensive (R)-amino acids is (R)-phenylglycine (formula 1), which is a precursor to (R)-4-phenyl-5,5-disubstituted oxazaborolidines of formula B. (R)-phenylglycine is relatively cheap because it is manufactured on a multi-ton scale as an intermediate in the synthesis of penicillin G. However, (R)-4-phenyl-5,5-disubstituted oxazaborolidines of formula B that are derived 
from (R)-phenylglycine are often not especially efficient chiral accessories, as they can lead to lower enantiomeric ratios in the borane reduction products of prochiral ketones. 
Common compounds of formulas A and Axe2x80x2 have the R1 substituent equal to an isopropyl or xe2x80x94(CH2)3xe2x80x94 group, with the terminal methylene moeity connected to the adjacent nitrogen atom on the ring (replacing a hydrogen atom) forming a five-membered ring. Unfortunately, the known compounds in the (R) configuration with R1 equal to, respectively, the isopropyl or xe2x80x94CH2)3xe2x80x94 group, are not inexpensive since they are derived from, respectively, (R)-valine and (R)-proline, which are relatively expensive synthetic amino acids. Prior attempts to produce quality, inexpensive chiral accessories of formula A with (R) or (S) configurations have only met with minimal success.
A goal achieved by this invention was to overcome these and other prior art problems. Accordingly, this invention, which includes novel, quality, inexpensive chiral accessories of the (R) or (S) absolute configurations, provides a superior benefit over the current art.
It is an object of this invention to provide inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
It is a further object of this invention to provide a process for producing inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
It is yet another object of this invention to reduce prochiral ketones enantioselectively to chiral secondary alcohols with inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
These and other objects of the present invention will become apparent after reading the following description and claims.
The term xe2x80x9cenantioselective catalyst,xe2x80x9d as used herein, means a compound which together with a borane reagent reduces a prochiral ketone to an optically active alcohol.
The term xe2x80x9cchiral accessory,xe2x80x9d as used herein, is synomous with the term xe2x80x9cenantioselective catalyst.xe2x80x9d
The term xe2x80x9cprochiral ketone,xe2x80x9d as used herein, means a ketone which on reduction can produce an optically active alcohol. Furthermore, a prochiral ketone will have structurally different moieties attached to its carbonyl group.
The term xe2x80x9calkyl,xe2x80x9d as used herein, means an unsubstituted or substituted, straight or branched, hydrocarbon chain. xe2x80x9cLower alkylxe2x80x9d has from 1 to 8 carbon atoms, preferably, from 1 to 4 carbon atoms.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, means an unsubstituted or substituted, saturated carbocyclic ring. xe2x80x9cLower cycloalkylxe2x80x9d has from 3 to 8 carbons.
The term xe2x80x9caryl,xe2x80x9d as used herein, means a substituted or unsubstituted aromatic carbocyclic ring. Preferred aryl groups include phenyl, tolyl, xylyl, cumenyl and napthyl.
The term xe2x80x9caralkyl,xe2x80x9d as used herein, means an alkyl moiety substituted with an aryl group. Preferred aralkyls include benzyl, phenylethyl, and 1- and 2-naphthylmethyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, means a straight or branched, hydrocarbon chain attached to an oxygen atom which is bonded to another atom of a compound. xe2x80x9cLower alkoxyxe2x80x9d has from 1 to 8 carbon atoms, preferably, from 1 to 4 carbon atoms.
The terms xe2x80x9csecondary chiral alcoholxe2x80x9d and xe2x80x9coptically active alcohol,xe2x80x9d as used herein, each mean an alcohol compound having a hydroxyl group attached to a carbon atom bearing a hydrogen atom and two other non-identical groups.
The term xe2x80x9csubstantially non-reactive substituent,xe2x80x9d as used herein, means a substituent that is not materially affected by either the reagents or solvents used during a chiral borane reduction of a ketone. That is, no significant side reactions occur involving the substituents, which would materially impair the optical and chemical efficacies of the compounds or processes at issue.
The term xe2x80x9cenantiomeric excessxe2x80x9d (ee), as used herein, means the excess amount of one enantiomer over the other enantiomer in a mixture of enantiomers, expressed in terms of percent, for example, a 9:1 ratio of R:S is equal to an 80% enantiomeric excess (ee) of (R).
The term xe2x80x9cborane reagent,xe2x80x9d as used herein, means a reagent that is a source of borane or supplies borane in a reaction. Typical reagents which are sources of borane include diborane gas (H3Bxe2x80x94BH3), borane-THF complex (in THF solution), borane dimethylsulfide complex and borane 1,4-oxathiane complex.
It is understood by those skilled in the art that the chiral accessories described herein exist in both the (R) and (S) absolute configurations. A (S) configuration refers to a counterclockwise arrangement of high to low priority substituents about an asymmetric carbon atom. A (R) configuration refers to a clockwise arrangement of high to low priority substituents about an asymmetric carbon atom. Compounds having (R) absolute configurations are specifically described herein. However, it is known to those skilled in the art that (S) configurations can also be produced from appropriately configured starting materials. The compounds described and claimed herein include their enantiomers, and solvates and salts thereof.
It is also known to a skilled artisan that the substituents defined in the compounds of the invention may themselves be substituted with a variety of groups, such as alkyl, cycloalkyl, aryl, aralkyl, hydroxy and alkoxy groups, or a variety of atoms, such as halogen atoms. These groups and atoms are substantially non-reactive substituents.
The invention relates to a compound having the formula I: 
where, the two R2 groups are identical and=substituted or unsubstituted, aryl, alkyl, cycloalkyl or aralkyl, and R3=H or substituted or unsubstituted, aryl, alkyl, aralkyl or alkoxy, for example, an alkoxy group, OR5, where R5 is a substituted or unsubstituted 20 alkyl group, and wherein the substituents on the R2 and R3 groups are substantially non-reactive.
This compound is useful as a chiral accessory.
The present invention also relates to a compound having the formula II: 
where, the R2 groups are defined the same as above for the compound of formula I, and wherein the substituents are substantially non-reactive.
The compounds of formula II are precursors that are useful for the preparation of the compounds of formula I. The invention further relates to a process for producing a compound having the formula I or II. The process comprises:
(a) reacting a (R or S)-cyclohexylglycine ester hydrochloride or hydrobromide compound having the formula III: 
xe2x80x83where, R4=alkyl and Y=Cl or Br, with an organometallic reagent having the formula R2MgX or R2Li, where, R2 is defined the same as above for the compound of formula I and X is Cl, Br or I, to form the compound of formula II, and
(b) reacting the compound of formula II formed in step (a) with (i) BH3, (ii) (BOR3)3 or R3B(OH)2 or (iii) B(OR5)3, respectively, where, R3 and R5 are defined the same as above for the compound of formula I, to form the compound of formula I, where, respectively, R3=(i) H, (ii) alkyl, aryl or aralkyl or (iii) OR5.
Furthermore, the present invention relates to a process for asymmetrically reducing prochiral ketones to secondary chiral alcohols, comprising reacting a prochiral ketone compound having the formula IV: 
where, RL and RS are non-identical, unsubstituted or substituted, aryl, alkyl, aralkyl or heteroaryl groups, with borane derived from a borane reagent, in the presence of a chiral accessory compound having the formula I according to the invention described above.
The compounds of the invention are represented herein without their absolute chiral configuration ((R) or (S)) or in the (R) configuration. The invention further encompasses compounds of the (S) configuration, as those skilled in the art know, for example, that compounds of formula I can exist in either the (R) or (S) absolute configuration, depending on the absolute configuration(s) of the starting material(s) from which they are prepared (e.g., compounds of formula II and III).
In the compounds of formula I, the two R2 groups are identical, preferably, substituted or unsubstituted, aryl or aralkyl, such as arylmethyls, more preferably, substituted or unsubstituted, phenyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthyl or 2-naphthyl, and most preferably, substituted or unsubstituted phenyl. Furthermore, in the compounds of formula I, R3 is, preferably, a hydrogen atom or a substituted or unsubstituted, alkyl, aryl, such as a phenyl group, aralkyl or alkoxy group, and more preferably, a hydrogen atom or a substituted or unsubstituted, lower alkyl (e.g., 1-8 carbon atoms) or lower alkoxy (e.g., 1-8 carbon atoms) group. Most preferably, R3 is a hydrogen atom or a methoxy, methyl or butyl group.
Representative formula I compounds are illustrated below: 
I.1: (R)-4-cyclohexyl-5,5-diphenyl-1,3,2-oxazaborolidine; 
I.2: (R)-4-cyclohexyl-5,5-diphenyl-2-methyl-1,3,2-oxazaborolidine; 
I.3: (R)-2-butyl-4-cyclohexyl-5,5-diphenyl-1,3,2-oxazaborolidine; 
I.4: (R)-4-cyclohexyl-2,5,5-triphenyl-1,3,2-oxazaborolidine; 
I.5: (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine; 
I.6: (R)-4-cyclohexyl-5,5-di(1-naphthylmethyl)-1,3,2-oxazaborolidine; 
I.7: (R)-4-cyclohexyl-5,5-di(1-naphthylmethyl)-2-methyl-1,3,2-oxazaborolidine; 
I.8: (R)-4-cyclohexyl-5,5-di(1-naphthylmethyl)-2-butyl-1,3,2-oxazaborolidine; 
I.9: (R)-4-cyclohexyl-5,5-di(1-naphthylmethyl)-2-phenyl-1,3,2-oxazaborolidine; 
I.10: (R)-4-cyclohexyl-5,5-di(1-naphthylmethyl)-2-methoxy-1,3,2-oxazaborolidine; 
I11: (R)-4-cyclohexyl-5,5-di(2-naphthylmethyl)-1,3,2-oxazaborolidine; 
I.12: (R)-4-cyclohexyl-5,5-di(2-naphthylmethyl)-2-methyl-1,3,2-oxazaborolidine; 
I.13: (R)-4-cyclohexyl-5,5-di(2-naphthylmethyl)-2-butyl-1,3,2-oxazaborolidine; 
I.14: (R)-4-cyclohexyl-5,5-di(2-naphthylmethyl)-2-phenyl-1,3,2-oxazaborolidine; 
I.15: (R)-4-cyclohexyl-5,5-di(2-naphthylmethyl)-2-methoxy-1,3,2-oxazaborolidine; 
I.16: (R)-4-cyclohexyl-5,5-dibenzyl-1,3,2-oxazaborolidine; 
I.17: (R)-4-cyclohexyl-5,5-dibenzyl-2-methyl-1,3,2-oxazaborolidine; 
I.18: (R)-4-cyclohexyl-5,5-dibenzyl-2-butyl-1,3,2-oxazaborolidine; 
I.19: (R)-4-cyclohexyl-5,5-dibenzyl-2-phenyl-1,3,2-oxazaborolidine; 
I.20: (R)-4-cyclohexyl-5,5-dibenzyl-2-methoxy-1,3,2-oxazaborolidine; 
I.21: (R)-4-cyclohexyl-5,5-di(1-naphthyl)-1,3,2-oxazaborolidine; 
I.22: (R)-4-cyclohexyl-5,5-di(1-naphthyl)-2-methyl-1,3,2-oxazaborolidine; 
I.23: (R)-4-cyclohexyl-5,5-di(1-naphthyl)-2-phenyl-1,3,2-oxazaborolidine; 
I.24. (R)-4-cyclohexyl-5,5-di(1-naphthyl)-2-methoxy-1,3,2-oxazaborolidine; 
I.25: (R)-4-cyclohexyl-5,5-di(2-naphthyl)-1,3,2-oxazaborolidine; 
I.26: (R)-4-cyclohexyl-5,5-di(1-naphthyl)-2-methyl-1,3,2-oxazaborolidine; 
I.27: (R)-4-cyclohexyl-5,5-di(2-naphthyl)-2-phenyl-1,3,2-oxazaborolidine; and 
I.28: (R)-4-cyclohexyl-5,5-di(2-naphthyl)-2-methoxy-1,3,2-oxazaborolidine.
The invention further includes the corresponding (S) enantiomers for the above depicted compounds of formula I. Likewise, the compounds having the formula II according to the invention are also represented herein in the (R) configuration, though it is understood by those skilled in the art that compounds of formula II, like with the compounds of formula I, can exist in the (S) configuration as well, depending on the configuration(s) of the starting material(s) from which they are prepared.
Like in the compounds of formula I, the two R2 groups in the compounds of formula II are identical, preferably, substituted or unsubstituted, aryl or aralkyl, for example, arylmethyl, more preferably, substituted or unsubstituted, phenyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthyl or 2-naphthyl groups. Most preferably, the two R2 groups are substituted or unsubstituted phenyl groups.
Representative formula II compounds are illustrated below: 
II.1: (R)-2-amino-2-cyclohexyl-1,1-diphenylethanol; 
II.2: (R)-2-amino-1,1-dibenzyl-2-cyclohexylethanol; 
II.3: (R)-2-amino-2-cyclohexyl-1,1-di(1-naphthylmethyl)ethanol; 
II.4: (R)-2-amino-2-cyclohexyl-1,1-di(2-naphthylmethyl)ethanol; 
II.5: (R)-2-amino-2-cyclohexyl-1,1-di(1-naphthyl)ethanol; and 
II.6: (R)-2-amino-2-cyclohexyl-1,1-di(2-naphthyl)ethanol.
The corresponding (S) enantiomers for the above depicted compounds of formula II are also encompassed by the invention.
A (R or S)-cyclohexylglycine ester hydrochloride or hydrobromide compound having the formula III may be used in the inventive process for producing a compound having the formula I. In step (a) of the inventive process, the reaction scheme advantageously proceeds as follows: 
where, R4=alkyl, preferably, lower alkyl (e.g., 1 to 8 carbon atoms); Y=Cl or Br; X=Cl, Br or I; and the R2 groups are identical and=substituted or unsubstituted, aryl, alkyl, cycloalkyl or aralkyl
An excess of a suitable organometallic reagent, R2MgX or R2Li (as a solution in an inert solvent), preferably, from about 3 to 6 equivalents, most preferably, about 6 equivalents, is added, advantageously, under nitrogen, to a solution or suspension of the (R or S)-cyclohexylglycine ester hydrochloride or hydrobromide compound having the formula III in an inert solvent, preferably, a dry inert solvent. The preferred organometallic reagents are organomagnesium (Grignard) and organolithium reagents. The organometallic reagents (R2MgX or R2Li) useful in the inventive process are well-known in the art and are often commercially available or may be prepared from alkyl, cycloalkyl, aryl or aralkyl halides and by methods known in the art.
The preferred inert (i.e., non-reactive) solvents include tetrahydrofuran, diethyl ether, t-butylmethylether, dimethoxyethane, diethoxymethane, toluene, hexane, heptane, methylene chloride and mixtures thereof. The most preferred inert solvents are tetrahydrofuran, diethyl ether or a mixture of toluene and tetrahydrofuran. The reaction temperature is, preferably, from about xe2x88x9220xc2x0 C. to reflux, more preferably, from about xe2x88x9210 to +45xc2x0 C., and most preferably, from about 0 to +45xc2x0 C. The reaction is advantageously run until it is complete, which generally takes less than 24 hours, and is quenched by adding dilute aqueous acid. By-product metal salts can form and may be separated off by, for example, filtration or extraction. The product compound-containing mixture is advantageously in an alkaline state prior to recovery of the product. Preferably, the pH is adjusted to about 9 or higher and the product compound of formula II may be isolated and purified by techniques well-known to those skilled in the art, such as extraction, chromatography, crystallization, sublimation and the like.
In step (b) of the process described above to produce compounds of formula I, the reaction scheme advantageously proceeds through three different ways ((i), (ii) or (iii)), depending on the structure of the boron-containing reagent. First, for (i) BH3, the reaction scheme may proceed as follows: 
where, R2 is defined the same as above and the borane reagent results in R3=H.
For compounds of formula I, where R3 is a hydrogen atom, a solution of a compound of formula II in an inert solvent, preferably, a dry inert solvent, is reacted, advantageously, under nitrogen, with a reagent that provides a source of borane. Reagents which are sources of borane include diborane gas (H3Bxe2x80x94BH3), borane-tetrahydrofuran complex (in tetrahydrofuran solution), borane dimethylsulfide complex and borane 1,4-oxathiane complex. The preferred inert solvents include ethers, hydrocarbons and chlorinated hydrocarbons. The more preferred inert solvents include toluene, methylene chloride, tetrahydrofuran, diethyl ether, diethoxymethane and t-butylmethylether. The most preferred inert solvent is tetrahydrofuran. The preferred reaction temperature is from about xe2x88x9220 to +40xc2x0 C. The more preferred reaction temperature is from about xe2x88x9220xc2x0 C. to room temperature. The reaction is usually complete in less that 2 hours. Compounds of formula I, where R3 is a hydrogen atom, are usually not isolated and are, preferably, generated and used in a solution to effect the chiral reduction of a prochiral ketone.
Second, for (ii) (BOR3)3 or R3B(OH)2 in step (b) of the process described above to produce compounds of formula I, where R3 is an alkyl, aryl or aralkyl group, the reaction advantageously takes place accordingly to the following scheme: 
where, R2 is defined the same as above and R3=substituted or unsubstituted, alkyl, aryl or aralkyl.
For compounds of formula I, where R3 is an alkyl, aryl or aralkyl group, a solution of a compound of formula II in a inert solvent, preferably, a dry inert solvent, is reacted, advantageously, under nitrogen, with a trialkyl or triaryl boroxine or an alkyl or aryl boric acid. The solvent is, advantageously, distilled out and fresh dry solvent is added until the reaction is complete. The compound of formula I, where R3 is an alkyl, aryl or aralkyl group, may be isolated by removing all of the remaining solvent (e.g., by distillation) and purified by methods well-known in the art, such as distillation, crystallization and chromatography. The preferred inert solvents include ethers, such as tetrahydrofuran, and aromatic hydrocarbons, such as benzene, toluene and xylene. The more preferred inert solvents are tetrahydrofuran and toluene. The preferred reagents include trimethylboroxine, tri-n-butylboroxine, triphenylboroxine, methylboronic acid, butylboronic acid and phenylboronic acid. Most preferably, trimethyl boroxine, tri-n-butylboroxine and phenylboronic acid are used as the reagents. The compounds of formula I, where R3 is an alkyl, aryl or aralkyl group, need not be isolated, but may be prepared in a solution which is used in the chiral borane reduction of prochiral ketones.
Third, for (iii) B(OR5)3 in step (b) of the process described above to produce compounds of formula I, where R3 is, advantageously, substituted or unsubstituted alkoxy, for example, OR5, where R5 is an unsubstituted alkyl group, the reaction advantageously takes place accordingly to the following scheme: 
where, R2 is defined the same as above and R3=substituted or unsubstituted alkoxy, OR5, where R5 is a substituted or unsubstituted alkyl group.
For compounds of formula I, where R3 is an alkoxy group, a solution of a compound of formula II in a inert solvent, preferably, a dry inert solvent, is reacted, advantageously, under nitrogen, with a trialkyl borate. The solvent is distilled out and fresh dry solvent is added until the reaction is complete. The compound of formula I, where R3 is an alkoxy group, can be isolated by removing all of the remaining solvent by distillation and purified by methods well-known in the art, such as distillation, crystallization and chromatography. The preferred inert solvents are the same as defined above for where R3 is an alkyl, aryl or aralkyl group. The preferred reagents include trimethylborate and tri-n-butylborate. The compounds of formula I, where R3 is an alkoxy group, need not be isolated, but may be prepared in a solution which is used in the chiral borane reduction of prochiral ketones. The substituents on the R groups are substantially non-reactive.
The reaction for the asymmetric borane reduction of a prochiral ketone to a secondary chiral alcohol in the presence of a compound of formula I advantageously takes place accordingly to the following scheme: 
where, RL and RS are non-identical, unsubstituted or substituted, aryl, alkyl, aralkyl or heteroaryl groups; and R2 and R3 are defined the same as above formula I.
Moreover, in the inventive process for the asymmetric reduction of prochiral ketones to secondary chiral alcohols, RL is, preferably, a substituted or unsubstituted aryl group and RS is, preferably, a substituted or unsubstituted alkyl group, especially a halogenated alkyl group, such as CF3, CCl3, CH2Br or CH2Cl. More preferably, RL is a substituted or unsubstituted phenyl group, such as CF3-phenyl, and RS is CH2Br, CH2Cl or CH2OCH3.
Compounds of formula I are relatively unstable. Therefore, for optimum efficiency it is preferable, but not mandatory, to generate these materials in an inert solvent, such as tetrahydrofuran, under nitrogen, and under anhydrous conditions, from a compound of formula II and the appropriate (i) borane reagent, (ii) substituted boroxine or boric acid or (iii) borate, as is described above. The reaction may be accomplished without isolation of the compound of formula I. Thus, for compounds of formula I, where R3 is a (i) hydrogen atom, (ii) an alkyl, aryl or aralkyl group or (iii) an alkoxy group, a solution of a compound of formula II in an inert solvent is reacted with either (i) borane derived from a borane reagent, (ii) (BOR3)3 or R3B(OH)2 or (iii) B(OR5)3, respectively. Reagents that are sources of borane include, diborane gas (H3Bxe2x80x94BH3), borane-THF complex (in THF solution), borane-dimethylsulfide complex and borane 1,4-oxathiane complex. The preferred inert solvents include ethers, hydrocarbons and chlorinated hydrocarbons. The more preferred inert solvents include, tetrahydrofuran, diethyl ether, diethoxymethane, t-butylmethylether, toluene, xylene and methylene chloride The most preferred solvents are THF and toluene.
The subject reaction to form compounds of formula I in solution advantageously takes place with about 1 equivalent of the boron containing reagents. The preferred reaction temperature is from about xe2x88x9220 to +40xc2x0 C. The more preferred reaction temperature is from about xe2x88x9220xc2x0 C. to +20xc2x0 C. In cases where reagents of the type (BOR3)3, R3B(OH)2 or B(OR5)3 are used, distillation of the solvent may be required to complete the formation of the compound of formula I. The reaction is usually complete in less that 12 hours. After in-situ formation of the compound of formula I, where R3 is a hydrogen atom or a substituted or unsubstituted, alkyl, aryl, aralkyl or alkoxy group, a borane reagent is added, followed by an addition of a prochiral ketone, which may be added neat or as a solution in an inert solvent, either gradually or all at once. The reaction is usually carried out at a temperature of from about xe2x88x9240 to +50xc2x0 C., preferably, from about xe2x88x9220 to +50xc2x0 C., and most preferably, from about 0 to +45xc2x0 C.
A molar ratio of the compound of formula I to the prochiral ketone compound is, advantageously, from about 1:200 to 3:1. The optimum molar ratio of the compound of formula I to the prochiral ketone compound depends on the substrate, especially in cases where the prochiral ketone compound contains substituent groups that can complex with borane. The molar ratio of the prochiral ketone compound to the borane reagent is, preferably, from about 1:0.3 to 1:6. The precise reaction reagents and conditions (including the structure of the chiral catalyst compound of formula I and the reaction temperature, ratios of reagents and types of solvent(s) used) selected to achieve optimum enantioselectivity in the reduction of the prochiral ketone will depend on the structures of the RL and RS groups of the ketone of formula IV. When reduction of the ketone is substantially complete, usually in less than 2 hours, the chiral secondary alcohol product may be isolated by quenching the reaction with dilute aqueous acid and extracting the product into an organic solvent. The compound of formula II usually can be isolated from the aqueous phase, purified and reused. The chiral secondary alcohol product may be isolated from the organic phase and purified by techniques well-known to those skilled in the art, such as extraction, chromatography, distillation, crystallization and the like.
The general reaction pathways for producing the compounds of the invention in the (R) configuration are illustrated below: 
The (R)- and (S)-cyclohexylglycine acid addition salts (compounds of formula 4) and the (R)- and (S)-cyclohexylglycine lower alkyl (e.g., 1 to 8 carbon atoms) ester acid addition salts (compounds of formula III) are known in the art (see e.g., Annalen der Chemie, 523, p. 199 (1936)) or can be prepared by procedures well-known in the art, such as by catalytic hydrogenation of (R)- and (S)-phenylglycine (compounds of formula 1) and (R)- and (S)-phenylglycine lower alkyl ester acid addition salts (compounds of formula 2), respectively. Typically, the organometallic reagents, R2MgX (Grignard), for example, phenylmagnesiumchloride and 1-naphthylmagnesium bromide, and R2Li (organolithium), for example, phenyllithium, are either commercially available or can be prepared by methods known in the art. Generally, the borane, BH3, is delivered in the form of a borane reagent, such as diborane gas or borane complexed with either tetrahydrofuran or dioxane, or is complexed to a sulfide, for example, dimethylsulfide-borane complex or 1,4-oxathiane-borane complex, or is complexed to a bis-sulfide, for example, 1,2-bis-(t-butylthio)ethane-diborane complex or 1,2-bis-(benzylthio)butane-diborane complex. The alkyl, aryl or aralkylboronic acid, [R3(OH)2], trialkyl, triarylborate or triaralkyl borate, [B(OR5)3], and trialkyl, triaryl or triaralkyl boroxine, [(BOR3)3], reagents are also either commercially available or can be prepared by methods known in the art.
The inventive compounds of formula I are useful as chiral accessories. Chiral alcohols are advantageously prepared by reacting a borane reagent with a prochiral ketone in the presence of the inventive chiral accessories as defined by formula I. These chiral accessories advantageously serve as enantioselective catalysts for the borane reduction of prochiral ketones to chiral alcohols. The compounds of formula II of the invention are useful as precursors for preparing the compounds of formula I. Some useful chiral intermediates and chiral compounds that are prepared with the aid of the chiral accessories of the invention and some representative inventive processes are shown below. Other useful intermediates and compounds will be evident to those skilled in the art. 